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1.  Neuronal and behavioural modulations by pathway-selective optogenetic stimulation of the primate oculomotor system 
Nature Communications  2015;6:8378.
Optogenetics enables temporally and spatially precise control of neuronal activity in vivo. One of the key advantages of optogenetics is that it can be used to control the activity of targeted neural pathways that connect specific brain regions. While such pathway-selective optogenetic control is a popular tool in rodents, attempts at modulating behaviour using pathway-selective optogenetics have not yet been successful in primates. Here we develop a methodology for pathway-selective optogenetics in macaque monkeys, focusing on the pathway from the frontal eye field (FEF) to the superior colliculus (SC), part of the complex oculomotor network. We find that the optogenetic stimulation of FEF projections to the SC modulates SC neuron activity and is sufficient to evoke saccadic eye movements towards the response field corresponding to the stimulation site. Thus, our results demonstrate the feasibility of using pathway-selective optogenetics to elucidate neural network function in primates.
Pathway-selective optogenetics enables the precise control of neural activity in targeted pathways connecting specific brain regions. Here the authors provide the first demonstration that pathway-selective optogenetics can modulate neural activity and behaviour in non-human primates.
PMCID: PMC4595751  PMID: 26387804
2.  Reorganization of corticospinal tract fibers after spinal cord injury in adult macaques 
Scientific Reports  2015;5:11986.
Previous studies have shown that sprouting of corticospinal tract (CST) fibers after spinal cord injury (SCI) contributes to recovery of motor functions. However, the neuroanatomical mechanism underlying the functional recovery through sprouting CST fibers remains unclear. Here we investigated the pattern of reorganization of CST fibers below the lesion site after SCI in adult macaques. Unilateral lesions were made at the level between the C7 and the C8 segment. The extent of spontaneous recovery of manual dexterity was assessed with a reaching/grasping task. The impaired dexterous manual movements were gradually recovered after SCI. When anterograde tract tracing with biotinylated dextran amine was performed to identify the intraspinal reinnervation of sprouting CST fibers, it was found that the laminar distribution of CST fibers was changed. The sprouting CST fibers extended preferentially into lamia IX where the spinal motor neuron pool was located, to innervate the motor neurons directly. Instead, few, if any, CST fibers were distributed in the dorsal laminae. The present results indicate that CST fibers below the lesion site after SCI in macaques are reorganized in conjunction with the recovery of dexterous manual movements.
PMCID: PMC4487234  PMID: 26132896
3.  Morphological Study of the Accommodative Apparatus in the Monkey Eye 
For more than a century there has been debate concerning the mechanism of accommodation—whether the lens capsule or lens material itself determines the functional relationship between ciliary muscle contractility and lens deformation during refractive adaptation. This morphological study in monkey eyes investigates the composition and distribution of several connective tissue components in the accommodative apparatus relaying muscle force to lens organization. Elastin distributes on the marginal surface of the ciliary process. A zonule is composed of fibrillin produced by epithelial cells of the process. In the progress of extension over the posterior chamber, fibrils unite into strands and possess longitudinal plasticity. By induction of the elastin network, strands extend in a concentric direction covering the equatorial region of the capsule. Upon tethering to the lens, the strand ramifies into fibrils, penetrating deeply close to the epithelial layer of the lens and binding with the collagen of the intercellular spaces. Tight linkage of the zonule with the capsule transmits precise contractility. Inside the lens, the cortical layer's elastic connective tissue network forms widely spaced lamellae of crystalline fibers. In contrast, the central nuclear lamellae are tightly opposed. The accumulation of lamellae is greater in the anterior cortex than in the posterior, yielding a more variable anterior chamber depth in the visual axis. The plasticity of the zonule and connective tissue distribution inside the lens produces an adjustable configuration. Thus, tight linkage between the dynamism of the capsule with interaction of the lenticular flexibility provides a novel understanding of accommodation. Anat Rec, 298:630–636, 2015.
PMCID: PMC4350428  PMID: 25403484
accommodation; zonule; fibrillin; elastin; fibronectin; collagen
4.  Sporadic Premature Aging in a Japanese Monkey: A Primate Model for Progeria 
PLoS ONE  2014;9(11):e111867.
In our institute, we have recently found a child Japanese monkey who is characterized by deep wrinkles of the skin and cataract of bilateral eyes. Numbers of analyses were performed to identify symptoms representing different aspects of aging. In this monkey, the cell cycle of fibroblasts at early passage was significantly extended as compared to a normal control. Moreover, both the appearance of senescent cells and the deficiency in DNA repair were observed. Also, pathological examination showed that this monkey has poikiloderma with superficial telangiectasia, and biochemical assay confirmed that levels of HbA1c and urinary hyaluronan were higher than those of other (child, adult, and aged) monkey groups. Of particular interest was that our MRI analysis revealed expansion of the cerebral sulci and lateral ventricles probably due to shrinkage of the cerebral cortex and the hippocampus. In addition, the conduction velocity of a peripheral sensory but not motor nerve was lower than in adult and child monkeys, and as low as in aged monkeys. However, we could not detect any individual-unique mutations of known genes responsible for major progeroid syndromes. The present results indicate that the monkey suffers from a kind of progeria that is not necessarily typical to human progeroid syndromes.
PMCID: PMC4218851  PMID: 25365557
5.  Marchiafava-Bignami disease with hyperintensity on late diffusion-weighted imaging 
Acta Radiologica Short Reports  2014;3(7):2047981614543284.
A 69-year-old man with a decades-long history of chronic alcohol consumption was admitted with gait disturbance (short steps and spasticity), deterioration of activity, and stuporous consciousness. Head magnetic resonance imaging (MRI) revealed hyperintensity on fluid-attenuated inversion recovery imaging in the corpus callosum and frontal white matter. The lesion later became more apparent on diffusion-weighted imaging. The clinical diagnosis was Marchiafava-Bignami disease (MBD). As temporary treatment, refraining from alcohol consumption and administration of vitamins were prescribed. The condition of the patient gradually improved. The purposes of this study were to demonstrate the clinical and radiological variety of MBD and to identify practical methods of treatment of this pathology.
PMCID: PMC4184409  PMID: 25298877
Marchiafava-Bignami disease (MBD); late diffusion-weighted imaging; white-matter lesions
6.  Methamphetamine Increases Locomotion and Dopamine Transporter Activity in Dopamine D5 Receptor-Deficient Mice 
PLoS ONE  2013;8(10):e75975.
Dopamine regulates the psychomotor stimulant activities of amphetamine-like substances in the brain. The effects of dopamine are mediated through five known dopamine receptor subtypes in mammals. The functional relevance of D5 dopamine receptors in the central nervous system is not well understood. To determine the functional relevance of D5 dopamine receptors, we created D5 dopamine receptor-deficient mice and then used these mice to assess the roles of D5 dopamine receptors in the behavioral response to methamphetamine. Interestingly, D5 dopamine receptor-deficient mice displayed increased ambulation in response to methamphetamine. Furthermore, dopamine transporter threonine phosphorylation levels, which regulate amphetamine-induced dopamine release, were elevated in D5 dopamine receptor-deficient mice. The increase in methamphetamine-induced locomotor activity was eliminated by pretreatment with the dopamine transporter blocker GBR12909. Taken together, these results suggest that dopamine transporter activity and threonine phosphorylation levels are regulated by D5 dopamine receptors.
PMCID: PMC3796526  PMID: 24155877
7.  Loss of DARPP-32 and calbindin in multiple system atrophy 
Journal of Neural Transmission  2013;120(12):1689-1698.
We evaluated the immunohistochemical intensities of α-synuclein, phosphorylated α-synuclein (p-syn), dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), calbindin-D 28k, calpain-cleaved carboxy-terminal 150-kDa spectrin fragment, and tyrosine hydroxylase in multiple system atrophy (MSA). The caudate head, anterior putamen, posterior putamen, substantia nigra, pontine nucleus, and cerebellar cortex from six MSA brains, six age-matched disease control brains (amyotrophic lateral sclerosis), and five control brains were processed for immunostaining by standard methods. Immunostaining for α-synuclein, p-syn, or both was increased in all areas examined in oligodendrocytes in MSA. Immunostaining for DARPP-32 and calbindin-D 28k was most prominently decreased in the posterior putamen, where neuronal loss was most prominent. Immunostaining for DARPP-32 and calbindin-D 28k was also diminished in the anterior putamen and caudate head, where neuronal loss was less prominent or absent. Calbindin immunostaining was also decreased in the dorsal tier of the substantia nigra and cerebellar cortex. Loss of immunostaining for DARPP-32 and calbindin-D 28k compared with that of neurons indicates calcium toxicity and disturbance of the phosphorylated state of proteins as relatively early events in the pathogenesis of MSA.
PMCID: PMC3834182  PMID: 23715974
Multiple system atrophy; DARPP-32; Calbindin-D 28k; Glial cytoplasmic inclusion; Pathogenesis
8.  Elucidating information processing in primate basal ganglia circuitry: a novel technique for pathway-selective ablation mediated by immunotoxin 
Employing a neuron-specific retrograde gene-transfer vector (NeuRet vector), we have recently developed a novel technique that achieves pathway-selective ablation in the primate brain. This technique is mediated by immunotoxin (IT) and eliminates a neuronal population that constitutes a particular pathway, leaving other pathways intact. By means of this technique, we have made an attempt to remove the hyperdirect pathway selectively from basal ganglia circuitry. The hyperdirect pathway links the motor cortex to the subthalamic nucleus (STN) directly and plays a crucial role in motor control. After electrical stimulation in the motor cortex, triphasic responses consisting of an early excitation, an inhibition, and a late excitation are usually elicited in the internal pallidal segment (GPi). Several pieces of pharmacophysiological evidence imply that the early excitation may be derived from the hyperdirect pathway. In our experiments, the NeuRet vector expressing human interleukin-2 receptor α-subunit was injected into the STN of macaque monkeys. Then, IT injections were performed into the supplementary motor area (SMA). When single neuron activity in the GPi was recorded in response to the SMA stimulation, it was found that the early excitation was significantly reduced with neither the inhibition nor the late excitation affected. The spontaneous firing rate and pattern of GPi neurons remained to be altered. This clearly indicates that IT-mediated tract targeting successfully eliminated the hyperdirect pathway with spontaneous activity of STN neurons unaffected. The electrophysiological findings were histologically confirmed by retrograde and anterograde neuronal labeling. The overall data define that the motor cortically driven early excitation in GPi neurons is conveyed through the hyperdirect pathway. The IT-mediated pathway-selective ablation technique will provide a powerful tool for elucidating information processing in various neural networks.
PMCID: PMC3760290  PMID: 24027499
basal ganglia; hyperdirect pathway; information processing; immunotoxin; lentivirus; vectors; gene transfer; primates
9.  Multisynaptic Inputs from the Medial Temporal Lobe to V4 in Macaques 
PLoS ONE  2012;7(12):e52115.
Retrograde transsynaptic transport of rabies virus was employed to undertake the top-down projections from the medial temporal lobe (MTL) to visual area V4 of the occipitotemporal visual pathway in Japanese monkeys (Macaca fuscata). On day 3 after rabies injections into V4, neuronal labeling was observed prominently in the temporal lobe areas that have direct connections with V4, including area TF of the parahippocampal cortex. Furthermore, conspicuous neuron labeling appeared disynaptically in area TH of the parahippocampal cortex, and areas 35 and 36 of the perirhinal cortex. The labeled neurons were located predominantly in deep layers. On day 4 after the rabies injections, labeled neurons were found in the hippocampal formation, along with massive labeling in the parahippocampal and perirhinal cortices. In the hippocampal formation, the densest neuron labeling was seen in layer 5 of the entorhinal cortex, and a small but certain number of neurons were labeled in other regions, such as the subicular complex and CA1 and CA3 of the hippocampus proper. The present results indicate that V4 receives major input from the hippocampus proper via the entorhinal cortex, as well as “short-cut” pathways that bypass the entorhinal cortex. These multisynaptic pathways may define an anatomical basis for hippocampal-cortical interactions involving lower visual areas. The multisynaptic input from the MTL to V4 is likely to provide mnemonic information about object recognition that is accomplished through the occipitotemporal pathway.
PMCID: PMC3525540  PMID: 23272220
10.  Immunotoxin-Mediated Tract Targeting in the Primate Brain: Selective Elimination of the Cortico-Subthalamic “Hyperdirect” Pathway 
PLoS ONE  2012;7(6):e39149.
Using a neuron-specific retrograde gene-transfer vector (NeuRet vector), we established immunotoxin (IT)-mediated tract targeting in the primate brain that allows ablation of a neuronal population constituting a particular pathway. Here, we attempted selective removal of the cortico-subthalamic “hyperdirect” pathway. In conjunction with the direct and indirect pathways, the hyperdirect pathway plays a crucial role in motor information processing in the basal ganglia. This pathway links the motor-related areas of the frontal lobe directly to the subthalamic nucleus (STN) without relay at the striatum. After electrical stimulation in the motor-related areas such as the supplementary motor area (SMA), triphasic responses consisting of an early excitation, an inhibition, and a late excitation are usually detected in the internal segment of the globus pallidus (GPi). Several lines of pharmacophysiological evidence suggest that the early excitation may be derived from the hyperdirect pathway. In the present study, the NeuRet vector expressing human interleukin-2 receptor α-subunit was injected into the STN of macaque monkeys. Then, IT injections were made into the SMA. In these monkeys, single-neuron activity in the GPi was recorded in response to the SMA stimulation. We found that the early excitation was largely reduced, with neither the inhibition nor the late excitation affected. The spontaneous firing rate and pattern of GPi neurons remained unchanged. This indicates that IT-mediated tract targeting successfully eliminated the hyperdirect pathway selectively from the basal ganglia circuitry without affecting spontaneous activity of STN neurons. The electrophysiological finding was confirmed with anatomical data obtained from retrograde and anterograde neural tracings. The present results define that the cortically-driven early excitation in GPi neurons is mediated by the hyperdirect pathway. The IT-mediated tract targeting technique will provide us with novel strategies for elucidating various neural network functions.
PMCID: PMC3382612  PMID: 22761729
11.  Ischaemia in the Zinn–Haller circle and glaucomatous optic neuropathy in macaque monkeys 
To elucidate the morphological features of optic neuropathy in an ischaemic model of glaucoma in macaque monkeys.
The regional degenerative process was investigated by experimentally occluding the paraoptic branches of the lateral short posterior ciliary artery, that is, the circle of Haller and Zinn, in 11 eyes. Morphological changes in nerve fibres in the lamina cribrosa were evaluated by histopathology, immunocytochemistry and angiography, and the findings were compared with those observed in an aged macaque with spontaneous glaucomatous optic neuropathy.
Retinal ganglion cell axons were grouped in bundles and traversed through pores in columns of the lamina cribrosa. The processes of astrocytes extended to the bundles, and capillaries branched in surrounding connective tissue from the circular arterioles. Experimental ischaemia induced time-dependent anoxic deterioration of phosphorylated fibres in the temporal arcuate zone, accompanied by glial proliferation. A monkey with spontaneous visual impairment had nerve fibre loss and gliosis with collagenous proliferation in the temporal hemisphere, suggesting glaucomatous neuropathy.
Circulatory interference in the circle of Haller and Zinn caused time-dependent deterioration in the area where anoxic segmental degeneration is associated with pathogenesis of open-angle glaucoma.
PMCID: PMC3308474  PMID: 22223748
Experimental glaucoma; circle of Haller and Zinn; ischaemic optic neuropathy; macaque glaucoma; glaucoma
12.  A Neural Correlate of the Processing of Multi-Second Time Intervals in Primate Prefrontal Cortex 
PLoS ONE  2011;6(4):e19168.
Several areas of the brain are known to participate in temporal processing. Neurons in the prefrontal cortex (PFC) are thought to contribute to perception of time intervals. However, it remains unclear whether the PFC itself can generate time intervals independently of external stimuli. Here we describe a group of PFC neurons in area 9 that became active when monkeys recognized a particular elapsed time within the range of 1–7 seconds. Another group of area 9 neurons became active only when subjects reproduced a specific interval without external cues. Both types of neurons were individually tuned to recognize or reproduce particular intervals. Moreover, the injection of muscimol, a GABA agonist, into this area bilaterally resulted in an increase in the error rate during time interval reproduction. These results suggest that area 9 may process multi-second intervals not only in perceptual recognition, but also in internal generation of time intervals.
PMCID: PMC3083430  PMID: 21556372
13.  Evaluation of cardiac resynchronization therapy in drug-resistant idiopathic dilated cardiomyopathy by means of technetium-99m tetrofosmin electrocardiography-gated single-photon emission computed tomography 
The present case report describes a 72-year-old woman with drug-resistant heart failure. Cardiac resynchronization therapy was performed. Cardiac function was evaluated using a quantitative gated single-photon emission computed tomography (QGS) program with technetium-99m tetrofosmin. During atrial-right ventricular pacing, the left ventricular ejection fraction (LVEF) was 28%, end diastolic volume (EDV) was 141 mL and end systolic volume (ESV) was 101 mL. LVEF was 31%, EDV was 142 mL and ESV was 98 mL during dual chamber pacing. During atrial-left ventricular pacing, LVEF, EDV and ESV were 32%, 18 mL and 100 mL, respectively. Diastolic function was evaluated using Vcdiff software (Daiichi Radioisotope Laboratories Ltd, Japan). Cardiac resynchronization therapy may improve cardiac function, which was evaluated accurately and non-invasively by electrocardiography-gated single-photon emission computed tomography.
PMCID: PMC2716286  PMID: 19641716
Cardiac function; Cardiac resynchronization therapy; Quantitative gated SPECT

Results 1-13 (13)